Project Abstract Disorders involving social behaviors such as autism spectrum disorder are increasingly prevalent, yet the pathophysiological bases for these conditions elude researchers and current treatments are woefully inadequate. The insular cortex and the neuropeptide oxytocin are highly implicated in both normal and pathological social affective processes such as empathy. Importantly, the oxytocin receptor is concentrated in the insular cortex, providing a link between these neural systems. Using a simple test of social affect in rat, we propose a multidisciplinary approach to determine the contribution and interaction of these systems in primitive, empathy-like processes. We hypothesize that social affective behavior in rodents involves axonal release of oxytocin acting at insular cortex oxytocin receptors and communication between the insula and other nodes in the social emotional circuit, namely the ventromedial prefrontal cortex. We seek to test this hypothesis in a number of ways. First, we will determine if insular cortex oxytocin receptors are necessary to social affective behavior using behavioral pharmacology and chemogenetics, quantify socially evoked oxytocin release within insula using in vivo microdialysis, identify the consequences of OT on the intrinsic excitability of prefrontal cortex-projecting insular pyramidal neurons and a generate a functional map of neuronal activation resulting from social affect using immunohistochemistry. Next we will chemogenetically manipulate the oxytocinergic input to the insula to determine if axonal release of oxytocin is sufficient to modulate social behaviors. Finally, we will utilize a multi-site, pathway specific chemogenetic strategy to dissect the contribution of insular cortex outputs to the prefrontal cortex in social affect, and their dependency on oxytocin. The expected contribution of this work will be to link release of oxytocin and action at insular cortex oxytocin receptors to social affective behaviors, via modulation of the insular cortex output to the prefrontal cortex. This work can have a transformative impact on our understanding of fundamental social behaviors, inform the development of new treatments of social disorders, and provide mechanistic support for theoretical models of the social brain.